PLA2 (phospholipases A2) are enzymes that can hydrolyze the fatty acyl ester bond at the sn-2 position of glycerophospholipid. After hydrolysis, free fatty acids are then formed, including arachidonic acid, and lysed glycerolipids. Arachidonic acid is the precursor for all prostaglandins and leukotrienes synthesis. Therefore, this enzyme family is related to inflammation. Particularly, secreted PLA2 (sPLA2) and cytosolic PLA2 (sPLA2) are the two most notable families, which are both Ca2+-dependent. In this essay, we will focus on sPLA2 and its inhibitors.

sPLA2 catalyzes the first step of the arachidonic acid pathway forming fatty acids, to promote inflammation. sPLA2 is involved in various inflammatory or immune diseases, such as asthma, pancreatitis, and coronary artery disease. According to research, sPLA2-deficient mice markedly reduce pulmonary inflammation compared with wild-type mice. Thus, sPLA2 inhibitors have the potential to suppress inflammatory symptoms.

CAY10590 (GK115) is a potent sPLA2 inhibitor.

This agent is based on (R)-γ-norleucine, possessing inhibitory activity against sPLA2 with an XI(50)* of 0.003. CAY10590 (1-10 μM, 24 h) can suppress prostaglandin E2 (PGE2) release in rat renal mesangial cells when co-incubated with IL-1β (1 nM) and Forskolin (5 μM). Similarly, in the human synovial sarcoma-derived cell line SW982, CAY10590 (10 μM, 24 h) completely blocks IL-1β-induced arachidonic acid release as well, with a reduction of 144.2 ± 3.8%. Besides, CAY10590 also dose-dependently reduces LPS-stimulated IP-10 release. Although there are few reports on this inhibitor, we think it may has the potential to play an effect on the treatment of inflammation.

In conclusion, CAY10590 is a potent and selectively sPLA2 inhibitor with inflammatory activity.

[1] Antonopoulou G, et al. Bioorg Med Chem. 2008 Dec 15;16(24):10257-69.
[2] Vasilakaki S, et al. Bioorg Med Chem. 2016 Jul 1;24(13):3029-3034.
[3] Sommerfelt RM, et al. PLoS One. 2015 Apr 20;10(4):e0119088.

*The XI(50) is the mole fraction of the inhibitor in the total substrate interface required to inhibit the enzyme by 50%.